rs397514752 — MYBPC3 Gly490Val

MYBPC3 Gly490Val — A Recessive Sarcomere Variant with Malignant Homozygous Phenotype

Cardiac myosin-binding protein C (cMyBP-C), encoded by MYBPC3 on chromosome 11, is a thick-filament accessory protein that accounts for roughly 2% of myofibrillar protein mass¹¹ roughly 2% of myofibrillar protein mass
cMyBP-C spans the C-zone of each sarcomere half and contacts both myosin and actin. Its C-terminal domains anchor it to the thick filament while its N-terminal domains regulate cross-bridge cycling — slowing myosin-actin interaction at rest and permitting contraction when phosphorylated by protein kinase A during adrenergic stimulation. MYBPC3 is the single most commonly mutated gene in hypertrophic cardiomyopathy (HCM), a condition marked by asymmetric left ventricular hypertrophy, diastolic dysfunction, and in severe cases, sudden cardiac death.

Most pathogenic MYBPC3 variants cause HCM through autosomal dominant haploinsufficiency — one defective copy is sufficient to disrupt sarcomere stoichiometry. The Gly490Val variant (rs397514752, c.1469G>T on the coding strand) is an important exception: it behaves recessively, causing disease only when both copies of MYBPC3 are affected.

The Mechanism

Glycine at position 490 falls within the C3 immunoglobulin-like domain²² C3 immunoglobulin-like domain
MYBPC3 contains 11 domains (C0-C10); C3 is an Ig-like domain in the middle segment of the protein of cMyBP-C. Glycine residues are structurally unique — their lack of a side chain allows tight turns and compact beta-strand arrangements that larger amino acids cannot adopt. Substituting the bulky valine disrupts this local fold. The conserved glycine at position 490 is present across vertebrate species, underscoring its structural importance.

In heterozygotes, one functional copy of MYBPC3 appears sufficient to maintain normal sarcomere stoichiometry, explaining why carriers remain phenotypically normal. In homozygotes, with no wild-type cMyBP-C produced, the sarcomere cannot regulate cross-bridge cycling properly, leading to the disorganized myocyte architecture (myofibre disarray) characteristic of severe HCM.

The Evidence

The variant was first reported in 2013 by Wang Y and colleagues³³ first reported in 2013 by Wang Y and colleagues
PLoS One, n=1 pedigree, 2 affected homozygous siblings, 5 unaffected heterozygous carriers, 376 controls in a consanguineous Chinese family. Both homozygous brothers presented with classic HCM: maximum wall thickness 17-18 mm, asymmetric ventricular hypertrophy on cardiac MRI, and diffuse repolarization changes with large negative T waves. None of the five adult heterozygous family members — including one aged 71 years — showed any clinical evidence of HCM by echocardiography or ECG. The variant was absent from 376 Chinese controls and public variant databases at the time of publication.

The recessive inheritance pattern at this site contrasts sharply with an adjacent variant, Gly490Arg, which causes dominant HCM. This domain-specific behavior illustrates how even nearby amino acid substitutions can produce fundamentally different inheritance modes depending on their effect on protein function versus stability.

Recessive MYBPC3 variants as a class are most dramatically illustrated by the Amish splice mutation, where homozygous infants developed lethal HCM requiring transplantation in the first year of life⁴⁴ homozygous infants developed lethal HCM requiring transplantation in the first year of life
Zahka K et al. Heart 2008; all surviving homozygous infants required cardiac transplantation, while heterozygous parents were unaffected. The Gly490Val variant appears to follow the same recessive pattern but with later onset and less catastrophic severity.

Evidence note: rs397514752 is reported in a single family (n=2 homozygous affected individuals). The evidence level is emerging — the recessive behavior is internally consistent and mechanistically plausible, but independent replication in additional families is needed before clinical management protocols can be established with confidence.

Practical Actions

For the overwhelming majority of people who carry this variant at all, the relevant question is whether they are heterozygous or homozygous. Heterozygous carriers have no current evidence of increased personal cardiac risk. Their clinical relevance lies in reproductive planning: if both members of a couple carry this variant, each pregnancy carries a 25% chance of producing a homozygous child with HCM.

Homozygous individuals warrant full cardiological evaluation given the documented severe phenotype.

Interactions

Because the pathogenic effect of rs397514752 is recessive, the key interaction is between the two copies of this variant in homozygotes — compound heterozygosity with a second MYBPC3 pathogenic variant on the other allele would likely produce a similar biallelic loss-of-function phenotype. Heterozygous carriers of rs397514752 who also carry a dominant MYBPC3 pathogenic variant on the opposite allele could theoretically have a modified phenotype, but no published evidence addresses this specific combination.